European mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy in AIDS Clinical Trials Group Study A5142
Todd Hulgan, Richard Haubrich, Sharon A Riddler, Pablo Tebas, Marylyn D Ritchie, Grace A McComsey, David W Haas, Jeffrey A Canter, Todd Hulgan, Richard Haubrich, Sharon A Riddler, Pablo Tebas, Marylyn D Ritchie, Grace A McComsey, David W Haas, Jeffrey A Canter
Abstract
Background: Mitochondrial DNA (mtDNA) influences metabolic diseases and perhaps antiretroviral therapy (ART) complications. We explored associations between European mtDNA haplogroups and metabolic changes among A5142 participants.
Methods: Seven hundred and fifty-seven ART-naive patients were randomized to one of three class-sparing ART regimens including efavirenz and/or lopinavir/ritonavir with or without nucleoside reverse transcriptase inhibitors (NRTIs). Nonrandomized NRTIs included stavudine, tenofovir, or zidovudine, each with lamivudine. Fasting lipid profiles and whole-body dual-energy X-ray absorptiometry (DEXA) were performed. Nine European mtDNA haplogroups were determined for 231 self-identified non-Hispanic white individuals. Metabolic changes from baseline to 96 weeks were analyzed by haplogroup.
Results: Median age was 39 years, 9% were women, and 37, 32, and 30 were randomized to NRTI-containing regimens with either efavirenz or lopinavir/ritonavir, and an NRTI-sparing regimen, respectively. Among NRTI-containing regimens, 51% included zidovudine, 28% tenofovir, and 21% stavudine. Compared with other haplogroups, mtDNA haplogroup I (N = 10) had higher baseline non-HDL cholesterol [160 mg/dl (interquartile range 137-171) vs. 120 mg/dl (104-136); P = 0.005], a decrease in non-HDL cholesterol over 96 weeks [-14% (-20 to 6) vs. +25% (8 to 51); P < 0.001], tended to have more baseline extremity fat, and had more extremity fat loss by DEXA [-13% (-13 to 12) vs. +9% (-13 to 26); P = 0.08] and lipoatrophy (50 vs. 20%; P = 0.04). Haplogroup W (N = 5; all randomized to NRTI-sparing regimens) had the greatest increase in extremity fat [+35.5% (26.8 to 54.9); P = 0.02].
Conclusions: Lipids and extremity fat were associated with European mtDNA haplogroups in this HIV-infected population. These preliminary results suggest that mitochondrial genomics may influence metabolic parameters before and during ART.
Trial registration: ClinicalTrials.gov NCT00050895.
Conflict of interest statement
Potential conflicts of interest:
Dr. Hulgan reports having received research support from Merck.
Dr. Haubrich reports having received speaking honoraria or consultant fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Merck, Schering and Roche and has received research support from Abbott, GlaxoSmithKline, Pfizer and Tibotec.
Dr. Riddler reports having received lecture or consultation fees from Bristol-Myers Squibb and grant support from Schering-Plough and Hoffman-LaRoche.
Dr. Tebas reports having received consultation fees from Glaxo, Merck, Pfizer and Tibotec.
Dr. Ritchie reports having received consultation fees from Boehringer-Ingelheim.
Dr. McComsey reports having received speaking honoraria or consultant fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Abbott and has received research support from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Gilead, and Abbott.
Dr. Haas has received research support from Bavarian Nordic, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Merck, and Tibotec, and has served on Scientific Advisory Boards for Boehringer-Ingelheim and Tibotec.
Dr. Canter reports no conflicts.
Figures
![Figure 1. Median percent changes in (a)…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2995830/bin/nihms244137f1a.jpg)
Figure 1. Median percent changes in (a)…
Figure 1. Median percent changes in (a) extremity fat by DEXA and (b) fasting non-HDL…
Figure 2. Proportion of subjects with lipoatrophy…
Figure 2. Proportion of subjects with lipoatrophy defined as ≥20% loss of extremity fat by…
Figure 2. Proportion of subjects with lipoatrophy…
Figure 2. Proportion of subjects with lipoatrophy defined as ≥20% loss of extremity fat by…
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- Research Support, N.I.H., Extramural
- Absorptiometry, Photon
- Adolescent
- Adult
- Aged
- Antiretroviral Therapy, Highly Active*
- Clinical Trials, Phase III as Topic
- DNA, Mitochondrial* / genetics
- Female
- HIV Infections / drug therapy*
- HIV Infections / genetics
- HIV Infections / metabolism
- HIV Protease Inhibitors / therapeutic use*
- HIV-1 / drug effects*
- HIV-1 / genetics
- HIV-Associated Lipodystrophy Syndrome / drug therapy*
- HIV-Associated Lipodystrophy Syndrome / genetics
- HIV-Associated Lipodystrophy Syndrome / metabolism
- Haplotypes / genetics
- Humans
- Male
- Middle Aged
- Retrospective Studies
- Reverse Transcriptase Inhibitors / therapeutic use*
- Sequence Analysis, DNA
- Young Adult
- DNA, Mitochondrial
- HIV Protease Inhibitors
- Reverse Transcriptase Inhibitors
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![Figure 1. Median percent changes in (a)…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2995830/bin/nihms244137f1b.jpg)
Figure 2. Proportion of subjects with lipoatrophy…
Figure 2. Proportion of subjects with lipoatrophy defined as ≥20% loss of extremity fat by…
Figure 2. Proportion of subjects with lipoatrophy…
Figure 2. Proportion of subjects with lipoatrophy defined as ≥20% loss of extremity fat by…
![Figure 2. Proportion of subjects with lipoatrophy…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2995830/bin/nihms244137f2a.jpg)
![Figure 2. Proportion of subjects with lipoatrophy…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2995830/bin/nihms244137f2b.jpg)
Source: PubMed